1. Description of Related Arts
Many new bioactive pharmaceutical compounds have solubility properties that can adversely affect drug bioavailability and efficacy. These compounds frequently lack either sufficient lipophilicity, reduced transdermal transport, or require some form of protective delivery matrix in order to improve performance. To address these issues many advanced delivery systems have been developed to improve solubility and enhance absorption. As a result, a panorama of such advanced delivery systems have evolved, and these approaches include cerasomes, dendrimers, liposomes, lipoids, micelles, nisosomes and polymeric micelles (US patent application 2012/0116064 by Dai, Liang and Yue; U.S. Pat. No. 6,579,906 to Cooper and Chen, issued Jun. 17, 2003; European Patent EP 0036277 to Papahadjopoulos, issued Aug. 28, 1985; U.S. Pat. No. 5,565,213 to Nakamori, Yoshida, et al., issued Oct. 15, 1996; U.S. Pat. No. 4,694,064 to Tomalia and Kirdhhoff, issued Sep. 15, 1987; U.S. Pat. No. 4,830,857 to Handjani, Ribier, et al., issued May 16, 1989). A review of many of these delivery mechanisms is given in Huynh, et al. Nanomedicine: Nanotechnol Biol and Med, 8, pp. 20-36 (2012), which is incorporated herein for reference.
Many systems derive enhanced attributes through the generation of colloid suspensions with suspended particulates having characteristic dimensions between 1 and 1,000 nm. Some examples of colloidal systems are emulsions, liposomes, microemulsions, multiple and multilayer emulsions, nanocrystal suspensions, solid lipid nanoparticles and polymeric particles [Madene A, Jacquot M, et al., Int J Food Sci Technol, 41, pp. 1-21 (2006); McClements D J, Adv Coll Interface Sci, 174, pp. 1-30 (2012); McClements D J, Decker E A, Weiss J, J Food Sci, 72, pp. R109-24 (2007); Muller R H, Gohla S, Keck C M, Eur J Pharm Biopharm, 78, pp. 1-9 (2011)]. However, transdermal delivery efficiency of many of these platforms (such as solid lipid nanoparticles) is reduced by the particle size achieved, which is often over 100 nm in diameter.
2. Background of the Invention
A key feature of many systems is the use of amphiphilic/semi-polar substances that exhibit both hydrophilic head groups and hydrophobic chain regions. In an aqueous environment, micelle particulates form from these amphiphilic substances with the polar regions facing out, interacting electrostatically with the aqueous phase, and the more hydrophobic regions, consisting of the hydrocarbon chains, facing inward. Such conditions are conducive for entrapment of hydrophobic bioactives within the hydrophobic matrix of the particulate structure. In environments where the oil phase is predominant, amphiphilic components reconform with hydrophobic regions external and hydrophilic regions being internalized.
And depending on the composition of the amphiphilic substances, packing of these molecules can be adjusted to form close packing to that of a looser configuration. In essence the behavior of such particulates can be polyphasic, having different phase configurations based the micelle concentration, composition of the liquid environment and amphiphilic components and temperature. Corkill and Goodman, Adv Colloid Interface Sci, 2, pp. 298-330 (1969) demonstrated that in aqueous solutions containing ampholytic components, the length of the alkyl chain greatly affected the concentration at which micelle formation occurred and the type and number of distinct morphic phases that might occur. The effect of increasing the molecular polarity was found to increase the temperatures necessary for different polymorphic phases to occur. Theoretical models have been developed that reflect the micellar structural phases observed and analyzed using low-angle X-ray diffraction [Lipinski, et al. Adv Drug Deliv Rev, 46, pp. 3-26 (2001); Jorgensen and Duffy, Adv Drug Del Rev, 54, pp. 355-366 (2002); Mannhold and Rekker, Perspect Drug Rev, 18, pp. 1-18 (2000)]. The complexity of conditions necessary to favor different phase formations and then to maintain a stable phase can present challenges to manufacture. The following examples are given to show the concerns with some new delivery systems that should be considered in the use and manufacture of such systems for drug delivery.
Liposomes, manufactured as vesicles of phospholipid bilayers encapsulating an aqueous space (0.03-10 μm diameter) have shown utility of use with a wide variety of drugs. However, hydrolysis or oxidation can degrade the liposomal integrity [Hunt and Tsang, Int J Pharm, 8, pp. 101-110 (1981)] and stability can be compromised due to aggregation, sedimentation of liposome fusion during storage [Wong and Thompson, Biochemistry, 21, pp. 4133-4139 (1982)]. Cerasomes demonstrate improvements over liposomes in regards to high stability towards surfactant solubilization, long term storage and acid treatment [Cao et al., Chem Commun, 46, pp. 5266-5267 (2010)]
Niosomes are non-ionic surfactants based multilamellar or unilamellar vesicles in which an aqueous solution of solute(s) is enclosed by a membrane resulted from the organization of surfactant macro-molecule as bilayer. Like liposomes, niosomes are also characterized by problems limiting shelf life due physical stability affected by aggregation, fusion and leaking [Hu and Rhodes, Int J Pharm, 206, pp. 110-122 (2000)].
Dendrimers also demonstrate potential for use with a wide range of different drug types. However, the system also demonstrates drawbacks in the complexity of dendrimer branch synthesis, the presence of branch defects and difficulties in purification after synthesis [Moses and Moorhouse, Chem Soc Rev, 36, pp. 1249-1262 (2007); Crooks, et al. Topics in Cur Chem, 212, pp. 81-135 (2001)].
Polymeric micelles are nanoscopic core/shell structures formed by amphiphilic block copolymers. They have good stability and good delivery transdermally. Polymers, however, are inherently heterogeneous and can be associated with changes in toxicity and drug efficacy [Duncan, Nature Reviews, 2, pp. 347-360 (2003)].
For transdermal delivery to be effective, system efficacy often requires enhancement through the use of penetration enhancers. The teachings from several patents support the premise that most pharmaceutically active substances can be introduced transdermally or intradermally with the use of penetration enhancers [U.S. Pat. No. 4,913,905 to Frankhauser issued April 1990; U.S. Pat. No. 4,917,676 to Heiber, issued April 1990; U.S. Pat. No. 5,032,403 to Sinnreich, issued July 1991]. Other enhancing components often include the addition of surfactants or chemical ingredients that modify skin barrier properties to increase transdermal flux. The relationship of such components and utilizations will be discussed in relation to this invention.